Pituitary Pars Intermedia Dysfunction (Equine Cushing’s Disease)

Pituitary Pars Intermedia Dysfunction (PPID) is the correct term
for the disease commonly known as Equine Cushing's Disease. The
latter term is technically incorrect because it is now known that
the disease is different from human Cushing's disease. It is a
condition of older horses and typically develops in horses over 15
years of age although it can develop in younger animals. Up to 30%
of aged horses have the condition and the risk of developing the
disease increases directly with age such that most horses in their
late 20's and even 30's will have the condition. The disease tends
to be seen more commonly in ponies but this may be because ponies
tend to live longer rather than because ponies are at greater risk
of the disease.

Aetiology

The condition is due to over-activity of one part (the
intermediate lobe) of the pituitary gland the excessive release of
certain metabolically active proteins and hormones. The pituitary
gland is located beneath the brain and releases its products in
response to signals from nerves that originate in another area of
the brain called the hypothalamus. Damage to these nerves causes
the pituitary to enlarge and produce excessive quantities of
hormones. The hormones known to be of importance are
adrenocorticropic hormone (ACTH), endorphins and melanocortins but
there are many others produced. The disease progresses gradually as
the nerves to the pituitary slowly degenerate. It is unknown how
the increases in pituitary hormones result in many of the clinical
signs that are seen.

Clinical Signs

Hirsutism is the term for excessive
hair growth or abnormal retention of the hair coat in the summer
and PPID is the only condition that causes this abnormality. The
presence of an abnormally long hair coat in an older horse is very
strong evidence of PPID (Figures 1 and 2).

Figure 1: Hirsutism and laminitis in an old
pony with PPID.

Figure 2: Curly coat typical of hirsutism in
a geriatric pony with PPID.

Abnormal fat deposition and
insulin resistance may develop in up to
60% of horses with PPID. The implications of insulin resistance are
discussed under Equine Metabolic Syndrome (EMS). Pituitary Pars
Intermedia Dysfunction and EMS are often confused as both
conditions result in insulin resistance; however, the reasons for
the insulin resistance are different. Furthermore, a number of
additional signs are seen with PPID. The differences between the
two conditions are discussed under EMS. A common site of increased
fat deposition is around the eyes.

Laminitis is the most serious
complication of PPID and is associated with considerable suffering
and potentially euthanasia. In the UK the majority of cases of
laminitis are caused by either EMS or PPID and PPID should
therefore be investigated in older horses that develop laminitis.
PPID should also be suspected if laminitis occurs in the autumn and
winter.

Figure 3: Neglected and laminitic feet in a
poorly managed pony with PPID.

Muscle wasting may be seen in some
cases and is usually most obvious over the hindquarters.

Increased drinking (polydipsia) and urination
(polyuria) may occur in up to a third of horses with
PPID; the reasons for this are unknown. There are many other causes
of increased drinking and urination but in an older horse
observation of these signs should prompt investigation of Cushing's
disease.

Increased sweating (hyperhidrosis) may
be seen even in horses that don't have an excessively long
haircoat.

Lethargy or a more docile temperament
may be observed and usually resolves with treatment.

Seizures, weakness, blindness and
collapse are seen rarely in advanced cases and are
thought to be the result of the enlarged pituitary putting pressure
on other areas of the brain.

Infertility may occur in mares as a
result of altered hormone production.

Infectious disease occurs more
commonly in horses with PPID compared to normal horses of the same
age because some of the hormones released with the condition
suppress the immune system. Common infections include ringworm,
sinus infection, pneumonia, and foot abscesses. Horses with PPID
are also more likely to have infections without showing clinical
signs and have been shown to be more susceptible to parasites.

Figure 4: Dental disease in a pony with
PPID.

Figure 5: Dermatophytosis (ringworm)
infection in a horse with PPID.

Diagnosis

Definitive diagnosis of PPID can be difficult as the changes in
the pituitary and the resultant blood and external changes can be
variable between animals. In addition there is a gradual
progression from normal to increased pituitary function making it
difficult to draw an arbitrary cut-off in classifying an animal as
diseased. Furthermore, pituitary function varies with season in all
horses and this has to be accounted for when testing is performed.
In advanced cases with marked hirsutism and other suggestive signs
the diagnosis may be made on clinical signs alone. Clinical
signs other than hirsutism are not a reliable means of making a
diagnosis but should prompt further testing.

Changes on routine blood samples are not specific for the
diagnosis of PPID but, as with clinical signs, they may give an
indication that the condition is present. Changes that may be seen
include high white cell counts and evidence of secondary infection,
high glucose and high liver enzymes. All of these changes have many
other potential explanations.

Specific diagnosis of PPID requires measurement of hormones in
the blood. This may be done on a single blood sample or the
pituitary gland's response to specific tests may be assessed.

Cortisol levels have traditionally
been used as an indicator of PPID. Cortisol is released from the
adrenal glands in response to increased hormone production from the
pituitary. Unfortunately horses with PPID often have normal
levels of cortisol and conversely normal horses may have high
levels if they are affected by pain, stress and other factors.
Levels of cortisol in urine and saliva have also been measured but
are unreliable.

Insulin levels are increased in 60% of
horses with PPID and may be an indicator of the severity of
disease. However, insulin levels are also high in horses with EMS
and horses that are painful, stressed or have recently been fed.
Therefore, further tests are required to distinguish PPID from
other potential causes of high insulin.

Adrenocorticotropic hormone (ACTH) is
released in increased quantities from the pituitary gland and
provides a reliable test for the diagnosis of PPID. The value of
the test has increased now that the normal seasonal changes in ACTH
levels are understood and differentiation of normal and abnormal is
more reliable. ACTH levels decrease rapidly in stored blood and it
is therefore important that samples are transported for analysis
rapidly and are kept frozen or chilled.

The Dexamethasone Suppression Test has
traditionally been regarded as the gold-standard test. More
recently however concerns have been expressed that this test is
unable to detect early cases of the disease and other tests may be
more sensitive. The test involves taking a blood sample to measure
natural cortisol, giving artificial cortisone (dexamathasone) and
then taking another blood sample the following day to see whether
natural cortisol levels have decreased. In horses with PPID there
is no reduction. Because more than one sample is required the test
is more expensive than testing ACTH. In addition, the test is
unreliable in late summer and the autumn when the pituitary gland
is naturally hyperactive.

The Thyrotropin Releasing Hormone (TRH) Stimulation
Test assesses the pituitary gland's response to
administration of TRH. In horses with PPID the pituitary gland has
an exaggerated response to TRH and increased levels of ACTH and
subsequently cortisol (released from the adrenal gland in response
to ACTH) can be identified in blood. Measurement of ACTH following
TRH stimulation is the most reliable. Unfortunately, TRH is very
expensive and hard to obtain limiting the availability of this
test.

Other tests are potentially available but are not used widely
because they fail to offer clear advantages over the ones already
described. These include the measurement of melanocyte stimulating
hormones, assessing the response to domperidone stimulation and
examining the pituitary gland using magnetic resonance imaging
(MRI) or computed tomography (CT).

Treatment

Fortunately effective treatment for PPID is available in the
form of pergolide and this drug has been
licensed specifically for horses recently. Pergolide stimulates
dopamine receptors in the brain and thereby replaces the activity
of the damaged nerve supply to the pituitary gland. This results in
reduction of hormone production to normal levels. The dose range is
wide and the improvement in clinical signs and ACTH levels is often
used to determine the best dose rate for each horse.

Cyprohepatidine is an anti-histamine that has a range of other
effects in the brain and has been suggested to be of use for PPID.
On its own it is not very effective but in some cases it may be
beneficial in association with pergolide. Trilostane is used for
the treatment of Cushing's disease in dogs but is not effective in
horses because of fundamental differences in the disease between
the two species.

A number of natural remedies have been suggested as treatments
for PPID but none have been proven to be effective. Only one, a
chasteberry (Vitex agnus castus) extract, has been tested in a
controlled manner and it failed to resolve clinical signs or
improve diagnostic test results in 14 horses. Subsequent treatment
of the same horses with pergolide was effective in all but one
case.

Horses with PPID require extra attention to be paid to dental
care, hoof care and parasite control. Those with dental disease may
benefit from cubed diets that are designed for older animals and
are easy to chew. Horses with excessive hair coat benefit from
regular clipping. Many horses with PPID develop insulin resistance
and this may need to be managed in much the same way as it is for
EMS (see the specific recommendations under EMS). With good
management there is no reason why horses with PPID cannot live a
long and normal life and continue in normal work.

Welfare Implications

The major welfare implication of this condition is the increased
risk of laminitis. Failure to provide adequate dental, hoof and
other routine care can also have a significant impact on the
welfare of affected animals.

Disease Control and Prevention

The disease is a natural degenerative condition and therefore
there is nothing that can be done to prevent it. Horses that are
kept in good health and have high levels of anti-oxidants may be
less likely to develop the nerve damage that is responsible for the
condition but this is unconfirmed. It has been suggested that
horses with EMS are more likely to develop the condition however
this is unproven. Similarly it has been suggested that feeding
anti-oxidants may be beneficial but there is some doubt whether
feeding anti-oxidants actually results in increased levels of
anti-oxidants in the brain. Early treatment with pergolide may slow
the progression of the disease but again this is unproven.

Summary of Key Learning Points

Pituitary Pars Intermedia Dysfunction is the correct term for
Equine Cushing's disease. This is a distinct condition from Equine
Metabolic Syndrome but the two diseases have some common
features.

PPID is a natural degenerative disease that affects older
horses

Normal nerve supply and therefore inhibition of the pituitary
is lost resulting in increased hormone production

A range of clinical signs may be seen. Hirsutism is the most
reliable indicator of the disease

Laminitis is the most serious clinical sign that develops

A number of diagnostic tests are available, the most commonly
used being measurement of ACTH and the Dexamethasone Suppression
Test

Pergolide is the most effective treatment

Prognosis is good with good management

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